EPA-540/1-86-009
Environmental Protection
Agency
Office of Emergency and
Remedial Response
Washington DC 20460
Superfund
£EPA
Office of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
HEALTH EFFECTS ASSESSMENT
FOR TETRACHLOROETHYLENE
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EPA/540/1-86-009
September 1984
HEALTH EFFECTS ASSESSMENT
FOR TETRACHLOROETHYLENE
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
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DISCLAIMER
This report has been funded wholly or In part by the UnHed States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and It has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with
tetrachloroethylene. All estimates of acceptable Intakes and carcinogenic
potency presented 1n this document should be considered as preliminary and
reflect limited resources allocated to this project. Pertinent toxlcologlc
and environmental data were located through on-Hne literature searches of
the Chemical Abstracts, TOXLINE, CANCERLINE and the CHEHFATE/DATALOG data
bases. The basic literature searched supporting this document 1s current up
to September, 1984. Secondary sources of Information have also been relied
upon In the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The
following Office of Health and Environmental Assessment (OHEA) sources have
been extensively utilized:
U.S. EPA. 1980b. Ambient Water Quality Criteria for Tetrachloro-
ethylene. Environmental Criteria and Assessment Office, Cincin-
nati, OH. EPA 440/5-80-073. NTIS PB 81-117830.
U.S. EPA. 1982. Hazard Profile for Tetrachloroethylene. Prepared
by the Environmental Criteria and Assessment Office, Cincinnati,
OH, OHEA for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1985. Health Assessment Document for Tetrachloroethyl-
ene {Perchloroethylene). Environmental Criteria and Assessment
Office, Research Triangle Park, NC. EPA 600/8-82-005F. NTIS PB
85-249704.
The Intent In these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer Is not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants 1n ambient air or water where lifetime exposure 1s
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
111
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The AIC, acceptable Intake chronic, 1s similar 1n concept to the ADI
(acceptable dally Intake). It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the llfespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable
exposure for a given route with the Implicit assumption that exposure by
other routes 1s Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development Is explained 1n U.S. EPA (1983).
For compounds for which there 1s sufficient evidence of carclnogenlcHy,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer 1s a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-|*s have been computed based on oral
and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment In proper context, the reader Is
referred to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates.
A major Issue of concern Is the potential carclnogenlclty of tetra-
chloroethylene. Human data are confounded by composite exposures. Results
of |£ vitro mutagenlclty bloassays are mixed. Only one animal bloassay
employing oral exposure has been conducted. Results In rats were negative.
In mice, tetrachloroethylene administration resulted 1n an Increased Inci-
dence of hepatocellular carcinoma. Using this data, a q-|* of 5.1xlO~2
(mg/kg/day)"1 was estimated.
The sole Inhalation cancer bloassay available to date employed rats and
failed to demonstrate an association between exposure to tetrachloroethylene
and Increased cancer Incidence. U.S. EPA (1985) using approplate pharma-
coklnetlc conversions estimated a unit risk of 4.8xlO~7
from the oral dose-response data.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball was^the Project
Officer. The final documents In this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
2.2.
ORAL
INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
TOXICANT INTERACTIONS
CARCINOGENICITY . •
4.1.
4.2.
4.3.
4.4.
REGUL
HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.2.3. Selected Pharacoklnetlcs Revelant to
Interspedes Extrapolation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
&TORY STANDARDS AND CRITERIA
Page
1
, . . 2
. . . 2
2
3
3
. . . 3
3
7
. . . 7
7
, , . 8
. . . 8
8
, , 8
10
. . . 10
. . . 10
10
10
. . . 10
. . . 11
11
. . . 13
, . . 15
. . . 16
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TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT 17
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 17
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 17
6.3. CARCINOGENIC POTENCY (q-j*) 17
6.3.1. Oral 17
6.3.2. Inhalation 20
7. REFERENCES 22
APPENDIX: Summary Table for Tetrachloroethylene 29
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LIST OF TABLES
No. Title
3-1 Summary of the Animal Effects of Subchronlc Inhalation
Exposure to Tetrachloroethylene
4-1 Disposition of "C-PCE Radioactivity for 72 Hours After
Single Oral Doses to Sprague-Dawley Rats and B6C3F] Mice. . . 12
6-1 Dose Response Data and Potency (Slope) Estimates 21
1x
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
CAS Chemical Abstract Service
CNS Central nervous system
CS Composite score
EEG . Electroencephalogram
LOAEL Lowest-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
tetrachloroethylene (CAS No. 127-18-4) are given as follows:
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Octanol/water partition
coefficient:
Soil mobility:
(predicted as retardation
factor for soil depth of
140 cm and organic carbon
content of 0.087%)
B1oconcentrat1on factor:
Halogenated aliphatic hydrocarbon
(purgeable halocarbon)
165.83
17.8 mm Hg at 25°C (U.S. EPA, 1982)
150 tug/I at 25°C (Ke1l, 1979)
398 (U.S. EPA, 1982)
2.5 (Wilson et a!., 1981)
Half-life 1n air:
Half-lives 1n water:
49 (1n blueglll, Lepomls macrochlrus)
(U.S. EPA, 1980b)
39 (1n rainbow trout, Salmo qalrdnerl)
(U.S. EPA, 1980b)
47 days (U.S. EPA, 1982)
1-7 days, calculated from reaeratlon rate
constant (Mabey et al., 1981)
10-25 days (Wakeham et al., 1983)
3-30 days (Zoeteman et al., 1980)
The half-life of tetrachloroethylene 1n soil could not be located 1n the
literature searched. However, evaporation Is expected to be the predominant
loss mechanism from the soil surface (Wilson et al., 1981). The half-life
for soil evaporation should be longer than Us evaporation half-life from
water (Wilson et al., 1981). In subsurface soil, no significant degradation
of tetrachloroethylene from soil 1s expected (Wilson et al., 1983); there-
fore, leaching of this compound from soil to groundwater 1s likely to occur.
-1-
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL MAMMALS
2.1. ORAL
Tetrachloroethylene Is absorbed to some extent from the gastrointestinal
tract (quantification and species not specified) (von Oettlngen, 1964).
Intestinal absorption by dogs 1s facilitated by fats and oils (Lamson et
a!., 1929).
2.2. INHALATION
The principal route by which tetrachloroethylene enters the human body
1s by pulmonary absorption 1n the alveolar air (U.S. EPA, 1985). Pulmonary
absorption of tetrachloroethylene Is rapid, and the amount of tetrachloro-
ethylene absorbed at a given vapor concentration (for exposures of <8 hours)
1s directly related to the respiratory minute volume (Hake and Stewart,
1977). von Oettlngen (1964) also reported that tetrachloroethylene 1s
readily absorbed through the lungs (quantification and species not
specified).
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Pertinent data regarding the subchronlc oral toxldty of
tetrachloroethylene could not be located 1n the available literature.
3.1.2. Inhalation. The effects of subchronlc Inhalation exposure to
tetrachloroethylene have been examined 1n rats, mice, rabbits, guinea pigs
and monkeys. These effects are summarized In Table 3-1.
Carpenter (1937) exposed three groups of albino rats to tetrachloro-
ethylene vapors at average concentration levels of 70, 230 or 470 ppm
(equivalent to 475, 1560 or 3188 mg/m3} for 8 hours/day, 5 days/week for 7
months. The control group consisted of 18 unexposed rats. After exposure
and a 46-day rest period, rats exposed to 470 ppm tetrachloroethylene had
cloudy and congested livers with swelling but no evidence of fatty degener-
ation or necrosis, Increased renal secretion with cloudy swelling and
desquamation of kidneys, and congested spleens with Increased pigment.
Following exposure to 230 ppm tetrachloroethylene and a 20-day rest period,
treated rats at this level had similar but less severe pathologic changes as
the highest exposure group. These changes Included renal and splenic
congestion and reduced hepatic glycogen storage. There was no evidence of
pathologic changes In the liver, kidneys or spleen of animals exposed to 70
ppm tetrachloroethylene for 7 months. Upon microscopic examination of rats
at each exposure level. Carpenter (1937) did not observe pathologic changes
in the heart, brain, eyes or nerve tissue. Functional parameters (Icteric
index, Van den Bergh test for blUrubin, blood and urine analysis) were
normal at all exposure levels. The fertility Index (actual number of
litters/possible number of litters) was Increased for female rats receiving
150 exposures of 230 or 470 ppm tetrachloroethylene. A NOEL of 70 ppm
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TABLE 3-1
Summary of the Animal Effects of Subchronlc Inhalation Exposure to Tetrachloroethylene
Species
Dose
(Concentration)
Exposure Period
Effects
Reference
Rats
Rats
IS ppm
70, 230 or
470 ppm
Rats
Mice
100-400 ppm
15-74 ppm
4 hours/day for
5 months
8 hours/day,
5 days/week, for
ISO exposures
(7 months)
7 hours/day,
5 days/week,
for 6 months
5 hours/day for
3 months
EEG changes and protoplasmal
swelling of cerebral cortical
cells, some vacuolated cells
and signs of karyolysls.
70 ppm: No pathological findings.
230 ppm: Similar, but less severe
pathological findings as with
higher dose; congestion and light
granular swelling of kidneys.
470 ppm: Congested livers with
cloudy swelling; no evidence of
fatty degeneration or necrosis;
evidence of kidney Injury Including
Increased secretion, cloudy swell-
Ing and desquamatlon; congestion
of spleen.
No abnormal growth, organ function
or hlstopathologlc findings.
Decreased electroconductance of
muscle and "amplitude" of muscular
contraction.
Dmltrleva, 1966
Carpenter, 1937
Rowe et al.,
1952
Dmltrleva, 1968
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TABLE 3-1 (cont.)
Species
Dose
(Concentration)
Exposure Period
Effects
Reference
Rabbits
Rabbits
Rabbits
Guinea
15 ppm
15 ppm
100-400 ppm
0. 100. 200
or 400 ppm
Monkeys
100-400 ppm
3-4 hours/day for
7-11 months
3-4 hours/day for
7-11 months
7 hours/day,
5 days/ueek,
for 6 months
7 hours/day,
5 days/ueek, for
132 or 169
exposures
7 hours/day,
5 days/ueek,
for 6 months
Depressed agglutlnln formation.
Moderately Increased urinary
uroblllnogen, pathomorphologlcal
changes In the parenchyma of
liver and kidneys.
No abnormal growth, organ function
or hlstopathologlc findings.
100 ppm: Increased liver weights
In females.
200 ppm: Increased liver weights
ulth some fatty degeneration In
both sexes; slight Increase In
hepatic llpld content; several
small fat vacuoles In liver.
400 ppm: More pronounced liver
changes than at 200 ppm; cirrhosis;
Increased liver weight; Increase
In neutral fat and ester If led
cholesterol In the liver; moderate
central fatty degeneration.
No abnormal growth, organ function
or hlstopathologlc findings.
Mazza, 1972
Navrotskll et
al., 1971
Roue et al.,
1952
Roue et al.,
1952
Roue et al.,
1952
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tetrachloroethylene for hepatic, renal and splenic pathologic changes In
rats can be derived from this study.
Rowe et al. (1952) exposed rats, rabbits, guinea pigs and monkeys to
tetrachloroethylene vapors at levels of 100-400 ppm for 7 hours/day, 5 days/
week for ~6 months. No abnormal growth, organ function or hlstopathologlc
findings were seen at any exposure level among treated rats, rabbits or
monkeys. Guinea pigs, however, were more susceptible to tetrachloro-
ethylene, with adverse effects occurring at all exposure levels. Female
guinea pigs exposed to tetrachloroethylene vapors at a level of 100 ppm had
Increased liver weights, while both sexes of guinea pigs exposed to 200 ppm
had Increased liver weights with some fatty degeneration, a slight Increase
In hepatic I1p1d content, and the presence of several small hepatic fat
vacuoles. Guinea pigs exposed to the highest exposure level used 1n this
study (400 ppm tetrachloroethylene) had more pronounced liver changes than
at the 200 ppm exposure level, Including cirrhosis, Increased Hver weight,
Increased hepatic neutral fat and esterlfled cholesterol, and moderate
hepatic central fatty degeneration. A LOAEL of 100 ppm tetrachloroethylene
for hepatic effects 1n guinea pigs can be derived from this study.
Four studies from the foreign literature (DmHrleva, 1966, 1968; Mazza,
1972; Navrotsk11 et al., 1971) of subchronlc Inhalation exposure to tetra-
chloroethylene were summarized by U.S. EPA (1985). EEG changes and proto-
plasmal swelling of cerebral cortical cells, and the presence of some vacuo-
lated cells and signs of karyolysls were seen In rats exposed to 15 ppm
tetrachloroethylene vapors, 4 hours/day for 5 months (Omltrleva, 1966).
Mice exposed to 15-74 ppm tetrachloroethylene for 5 hours/day for 3 months
had decreased electroconductance of muscle and "amplitude" of muscular
contraction (DmHrleva, 1968). Rabbits exposed to tetrachloroethylene
-6-
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vapors at a level of 15 ppm for 3-4 hours/day for 7-11 months had depressed
agglutinin formation (Mazza, 1972), and moderately Increased urinary uro-
blUnogen and pathomorphological changes in hepatic and renal parenchyma
(Navrotskii et a!., 1971). The lack of further details and dose-response
data in these four studies from the Russian literature precludes their use
for quantitative human risk assessment for inhalation exposure to tetra-
chloroethylene.
3.2. CHRONIC
3.2.1. Oral. The only source of information regarding chronic oral
toxicity resulting from exposure to tetrachloroethylene 1s the National
Cancer Institute (NCI, 1977) carcinogenidty bioassay with Osborne-Mendel
rats and B6C3F, mice. Groups of 50 male and 50 female rats and mice
received various levels of tetrachloroethylene in corn oil by gavage, 5
days/week for 78 weeks. TWA doses for this study were 450 and 550 mg/kg/day
for male mice, 300 and 400 mg/kg/day for female mice, 471 and 941 mg/kg/day
for male rats, and 474 and 949 mg/kg/day for female rats. Control groups
consisted of 20 male and 20 female animals of each species that were either
untreated or vehicle-treated. Toxic nephropathy was observed at all dose
levels in both sexes of mice and rats. Therefore, the LOAEL for toxic
nephropathy was 300 mg/kg/day for mice and 471 mg/kg/day for rats.
3.2.2. Inhalation. In a meeting abstract, Pegg et al. (1978) reported
the results of a disposition study in Sprague-Oawley rats following
inhalation exposure to tetrachloroethylene at a level of 4 g/m3 (600 ppm)
for 6 hours/day, 5 days/week for 12 months. Unspecified reversible liver
damage was observed 1n the treated rats.
Human health effects as a result of chronic inhalation exposure to
various concentrations of tetrachloroethylene include respiratory tract
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Irritation, nausea, headache, sleeplessness, abdominal pains and constipa-
tion (Chm1elewsk1 et al., 1976; Coler and Rossmlller, 1953; Stewart et al.,
1970; von Oettlngen, 1964). Liver cirrhosis, hepatitis and nephritis have
also been reported (Stewart, 1969). Side effects from the therapeutic use
of tetrachloroethylene as an antlhelmlntic agent also have been reported
(von Oettlngen, 1964). Lack of dose quantification and a dose-response
relationship precludes the use of these human data for quantitative risk
assessment for Inhalation exposure to tetrachloroethylene.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Pertinent data regarding the teratogenlclty of tetrachloro-
ethylene following oral administration could not be located In the available
literature.
3.3.2. Inhalation. Schwetz et al. (1975) exposed 17 pregnant Sprague-
Dawley rats and 17 pregnant Swiss-Webster mice to tetrachloroethylene by
Inhalation at a level of 300 ppm (2035 mg/m3) for 7 hours/day on days 6-15
of gestation. Caesarean sections were done on day 18 (mice) or 21 (rats).
Maternal rats had a statistically significant reduction 1n mean body weight,
while maternal mice had Increased mean relative liver weight. The fetal
body weight of mice was significantly depressed. A significantly Increased
number of rat fetuses were resorbed. For mice, the Incidences of subcutan-
eous edema, delayed ossification of skull bones, and split sternebrae were
significantly Increased, compared with those Incidences In control mice.
3.4. TOXICANT INTERACTIONS
Compounds that alter the functional activity of mlcrosomal enzyme
systems may affect the toxldty of tetrachloroethylene because H 1s metab-
olized by mixed function oxldases (U.S. EPA, 1980b). Phenobarbltal pre-
treatment, however, did not modify the acute hepatotoxldty of tetrachloro-
-8-
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ethylene (Cornish et al., 1973, 1977). Induction of mixed function oxldases
by pretreatment with Aroclor 1254 resulted In altered tetrachloroethylene
acute tox1c1ty, manifested by vacuollzatlon of rough endoplasmlc retlculum
and Increased serum glutamate oxalacetate transamlnase activity (Moslen et
al., 1977; Reynolds and Moslen, 1977).
Tetrachloroethylene has been associated with Intolerance to alcohol,
probably because both tetrachloroethylene and alcohol are CNS depressants
(Gold, 1969). Synerglstlc effects, Identified by lethality as the endpoint,
of mixtures of tetrachloroethylene and benzene following Intubation to rats
have been reported (Wlthey and Hall, 1975).
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding the cardnogenldty of orally
administered tetrachloroethylene to humans could not be located In the
available literature.
4.1.2. Inhalation. In a study of 330 deceased laundry and dry-cleaning
workers with a history of exposure to tetrachloroethylene, carbon tetra-
chlorlde and trlchloroethylene, Blair et al. (1979) observed an excess of
lung, cervical and skin cancers and a slight excess of leukemlas and liver
cancers. Blair et al. (1978) reported five cases of chronic lymphocytlc
leukemia among a family that operated a dry-cleaning business.
4.2. BIOASSAYS
4.2.1. Oral. The only source of cardnogenldty data from oral exposure
to tetrachloroethylene Is the NCI (1977) cardnogenldty bloassay with
Osborne-Mendel rats and B6C3F.. mice. Groups of 50 male and 50 female rats
and mice received various levels of tetrachloroethylene In corn oil by
gavage, 5 days/week, for 78 weeks. TWA doses for this study were 536 and
1072 mg/kg/day for male mice, 386 and 772 mg/kg/day for female mice, 471 and
941 mg/kg/day for male rats, and 474 and 949 mg/kg/day for female rats.
Control groups consisted of 20 male and 20 female animals of each spedes
that were either untreated or vehicle-treated. All surviving mice were
killed at 90 weeks and all surviving rats at 110 weeks. Decreased survival
rates were observed for both species. No Increases 1n tumor Incidences were
observed for treated rats. Mice, however, were observed to have highly
significant Increases 1n hepatocellular carcinomas. The Incidences of this
tumor type In mice were 2/17 untreated control males, 2/20 vehicle control
males, 32/49 low-dose males, and 27/48 high-dose males; and 2/20 untreated
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control females, 0/20 vehicle control females, 19/48 low-dose females, and
19/48 high-dose females. Metastases were reported for one untreated control
male, three low-dose males, one low-dose female and one high-dose female.
4.2.2. Inhalation. Rampy et al. (1977) exposed groups of 96 male and 96
female Sprague-Dawley rats to tetrachloroethylene vapors at levels of 2 or
4 g/m3 (300 or 600 ppm, respectively) for 6 hours/day, 5 days/week for 12
months. There was no statistically significant difference In any tumor
Incidence between treated and control animals.
4.2.3. Selected Pharmacoklnetlcs Relevant to Interspedes Extrapolation.
U.S. EPA (1985) evaluated the Pharmacoklnetlcs of tetrachloroethylene
relevant to Interspedes dose response extrapolation. The material In this
section 1s excerpted from U.S. EPA (1985). It Is generally recognized that
the carclnogenldty of the chlorinated ethylenes relates to their metabolic
conversion to biologically reactive Intermediates. The metabolism of tetra-
chloroethylene has been Investigated In the mouse, rat and man. In general,
the end metabolites have been poorly characterized across these species, and
there Is no experimental evidence which Indicates qualitative differences 1n
metabolic pathways.
Pharmacok1net1c/metabol1c evaluations following oral exposure considered
most relevant to species extrapolation Include Pegg et al. (1979), Schumann
et al. (1980), and Buben and O'Flaherty (1985).
Pegg et al (1979) and Schumann et al. (1980) administered 14C tetra-
chloroethylene In corn oil to Sprague-Dawley rats and B6C3F, mice as
single Intragastrlc doses of 1 or 500 mg/kg. i4C radioactivity was mea-
sured In exhaled breath, urine, feces and carcass for 72 hours following
dosing. In addition, pulmonary excretion of parent compound was monitored.
The results of these Investigations as presented by U.S. EPA (1985) are
shown In Table 4-1.
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TABLE 4-1
Disposition of "C-PCE Radioactivity for 72 Hours After Single Oral Doses to
Sprague-Dawley Rats and B6C3F] Mice3
Expired
unchanged
Metabolized
14C02
Urine
Feces
Carcass
Total
Rats
1 mg/kg
(0.25 mq/kq/anlmal)
mg-eq per animal
0.174 (71X)
0.007
0.040
0.015
0.008
0.070 (29%)
0.244
(average of 3}b
500 mg/kg
(125 mg/anlmal)
mg-eq per animal
110.67 (90X)
0.57
5.72
4.82
1.41
12.52 (10X)
123.19
Mice (average of 3}
500 mg/kg
(12.25 mq/anlmal)
mg-eq per animal
8.90 (83%)
0.14
1.53
0.13
0.05
1.85 (17X)
10.75
aSource: U.S. EPA, 1985
bfiased on average experimental animal weight (grams): 250, rat; 24.5, mouse.
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For rats, 29% and 10% of the 1 and 500 mg/kg doses, respectively was
metabolized, Indicating metabolism which 1s both limited and saturable. In
mice given 500 mg/kg 17% of the dose was metabolized. The ratio of the
metabolized dose In rats:m1ce calculated by U.S. EPA (1985) 1s 6.77. U.S.
EPA (1985) concluded that this relationship Indicated that the comparative
metabolism of tetrachloroethylene was more consistent with a surface area
than a body weight proportionality.
Buben and O'Flaherty (1985) examined tetrachloroethylene metabolism 1n
male mice dosed 5 days/week for 6 weeks by gavage using a corn oil vehicle.
They found that metabolism was both saturable and dose-dependent. Metabo-
lism was evaluated based on the level of urinary trlchloroacetlc add
(TCA). U.S. EPA (1985) judged that urinary TCA 1s expected to represent
70-80% of total tetrachloroethylene metabolized. The data from this study
are shown 1n Figure 4-1. Comparison of the amount metabolized from the
Schumann et al. (1980) and Pegg et al. (1979) studies where mice were given
500 mg/kg to the amount metabolized for a 500 mg/kg dose based on Figure 4-1
Indicates good agreement between the two studies. The molar equivalent
metabolized dose from Figure 1 (367 ymoles) represents 80% of the molar
equivalent metabolized dose (455 pmoles) from Schumann et al. (1980) and
Pegg et al. (1979).
4.3. OTHER RELEVANT DATA
Tetrachloroethylene elicited a positive response In both the Salmonella
typhlmurlum reverse mutation assay and the host-mediated assay In mice,
using S. typhlmurlum (Cerna and Kypenova, 1977). Tetrachloroethylene was
negative 1n forward mutation assays with Escherlchla coll (Grelm et al.,
1975) and failed to Induce chromosomal aberrations 1n bone marrow cells of
mice that had received 1 or 5 dally IntrapeMtoneal Injections of the com-
pound (Cerna and Kypenova, 1977).
-13-
-------
R* =0.98
= 136
ii|inuiiiHniiiiMntuiniinMirmmiiinnu|MtiMii
200 400 600 800 1000 1200 1400
1600 1800 2000
DOSE (mg/kg)
FIGURE 4-1
Relationship Between the PCE Dose and the Amount of Total Urinary Metabolite Excreted per Day
by Mice In Each Group
Source: U.S. EPA, 1985
-------
4.4. WEIGHT OF EVIDENCE
IARC (1979) concluded that there was limited evidence that tetrachloro-
ethylene 1s carcinogenic 1n mice, based on the Increased Incidence of
hepatocellular carcinomas 1n both sexes of mice following oral administra-
tion of tetrachloroethylene (NCI, 1977). Human cardnogenldty data, con-
sisting of a proportionate mortality study of 330 former laundry workers,
was considered to be Inadequate for assessing human cancer risk associated
with exposure to tetrachloroethylene (IARC, 1982). Likewise, the evidence
for tetrachloroethylene activity 1n short-term tests was considered Inade-
quate (IARC, 1982). Applying the criteria proposed by the Carcinogen
Assessment Group of the U.S. EPA for evaluating the overall weight of
evidence of cardnogenldty to humans (Federal Register, 1984), tetrachloro-
ethylene 1s most appropriately designated a Group C - Possible Human
Carcinogen.
-15-
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5. REGULATORY STANDARDS AND CRITERIA
ACGIH (1983) has recommended a TWA-TLV of 50 ppm and a STEL of 200 ppm.
OSHA has established a permissible exposure level (8-hour TWA) of 100 ppm
(Code of Federal Regulations, 1981).
-16-
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
Tetrachloroethylene 1s a chemical demonstrated to be carcinogenic 1n
animals, and for which data are sufficient for estimation of carcinogenic
potency. It 1s Inappropriate, therefore, to calculate an AIS for this
chemical.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
Tetrachloroethylene 1s a chemical demonstrated to be carcinogenic 1n
animals, and for which data are sufficient for estimation of carcinogenic
potency. It Is Inappropriate, therefore, to calculate an AIC for this
chemical.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. U.S. EPA (1985) based on the data of Buben and O'Flaherty
(1985) estimated the quantity of metabolites contributing to the carcino-
genic response for the NCI (1977) study 1n B6C3F1 mice as follows:
NCI Gavage
Dose (mq/kg/day)
536
1072
386
772
Urinary Metabolites
(mq TCA/kq/day)
60.95
84.18
50.19
73.32
% Increase
with Dose
38
46
Males
Females
Potency estimates expressed In terms of both metabolized and
administered dose are shown In Table 6-1. Potency 1n terms of administered
dose (A) was calculated from potency 1n terms of metabolized dose using the
relationship M=0.2A. This relationship was estimated by U.S. EPA (1985)
-17-
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TABLE 6-1
Dose Response Data and Potency (Slope) Estimates
GO
Nales
Females
Animal
Time -weighted
Average
Metabolized Dose
(ing/kg/day)3
0
37.73
52.11
0
31.07
45.39
Tumor
Incidence^
2/20
32/48
27/45
0/20
19/48
19/45
Human Potency
Estimate
In Terms of
Metabolized Dose
(mg/kg/dayr1
3.4x10-*
2.5xlO"2
Human Potency
Estimate
In Terms of
Administered Dosec
Img/kg/day)"1
6.8xlO~2
5.1xlO~2
Calculated from metabolized dose data shown In Table 4-1 by multiplying by 78 weeks/90 weeks and 5 days/
7 days
bThe denominators are the number of animals that survived at the time the first hepatocellular carcinoma
occurred In each study
cHuman potency estimates were calculated from animal potency estimates by multiplying by (we1ghtnuman/
-------
based on the data of Buben and O'Flaherty (1985). For comparative purposes,
potency was also calculated using metabolized dose estimated from the data
of Schumann et al. (1980). There was good agreement between the estimates
generated by the two methods. U.S. EPA (1985) recommended that the potency
estimate calculated from tumor Incidence In female mice, 5.1xlO~2
(mg/kg/day)'1, be used to represent the potency of tetrachloroethylene
because the dose-response data for female mice were "more reliable" than for
male mice.
6.3.2. Inhalation. In the only Inhalation cancer assay available to
date, Rampy et al. (1977) did not find any statistically significant
difference In any tumor Incidence between control rats and those exposed to
tetrachloroethylene vapors at levels of 2 or 4 g/m3 (300 or 600 ppm,
respectively), 6 hours/day, 5 days/week, for 12 months. U.S. EPA (1985)
calculated unit risks for Inhalation exposure using a variety of
pharmacoklnetlc approaches for route extrapolation. The unit risk of
4.8xlO~7 (yg/m3)"1 was recommended for use as the representative
estimate. This estimate was based upon the relationship between exposure
concentration and tetrachloroethylene metabolites 1n urine from the data of
Bolanowska and Golacka (1972). In the study, five subjects were exposed to
390,000 jig/m3 tetrachloroethylene for 6 hours. Metabolites 1n the urine
were monitored for 20 hours. The total amount of metabolites was estimated
to be 13 mg (U.S. EPA, 1985). The amount of metabolites up to 20 hours was
taken directly from the experimental data. The remainder of the area, under
the curve, 20 hours to Infinity, was estimated as:
CxT]/2/0.693
-19-
-------
where:
C = concentration of metabolites at the last sampling time
assumed to be 100 hours
Assuming that the amount metabolized 1s linearly related to the air
concentration and the duration of exposure, the amount metabolized
associated with 1 vg/m3 of tetrachloroethylene In air 1s:
(13 mg/39,000 mg/m3) x (24 hours/6 hours) = 1.33xlO~4 mg/day
or
1.9xlO~* mg/kg/day
The cancer risk associated with exposure to 1 yg/m3 tetrachloro-
ethylene 1s:
2.5X10"1 (mg/kg/day)'1 x 1.9xlO~6 mg/kg/day = 4.8xlO~7 (vg/m3)'1
Assuming a human breathes 20 m3 of air In 24 hours and weighs 70 kg,
this unit risk may be expressed as 1.68xlO~3 (mg/kg/day)"1.
-20-
-------
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-------
Chmlelewski, J., R. Tomaszewskl, P. Glomblowskl. et al. 1976. Clinical
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Gold, J.H. 1969. Chronic perchloroethylene poisoning. Can. Psychlat.
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-24-
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APPENDIX
Summary Table for Tetrachloruethylene
1
ro
00
i
Carcinogenic
Potency
Inhalation
Oral
Species
mice
mice
Experimental
Dose/Exposure
536-1072
mg/kg/day
536-1072
mg/kg/day
Effect
hepatocellular
carcinoma
hepatocellular
carcinoma
qi*
1.68xlO~a
5.1xlO~2
(mg/kg/day) 1
Reference
NCI, 1977;
U.S. EPA, 1985
NCI, 1977;
U.S. EPA, 1985
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